It is based on the crossover Alien vs Predator franchise, a concept which originated in a 1989 comic book published by Dark Horse Comics, and it centers around a group of archeologists lead by billionaire Charles Bishop Weyland, who investigate a heat signal coming from the Antartic. It was followed by Aliens vs. Predator: Requiem.

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In 2004, a satellite detects a mysterious heat bloom beneath Bouvetaya, an island about one thousand miles off the coast of Antartica. The wealthy industrialist Charles Bishop Weyland, owner of the satellite, assembles a team of scientists with the intention to investigate the heat source and claim it for his multinational communications company, Weyland Industries before another one does. The team includes archaeologists, linguistic experts, drillers, mercenaries, and a guide named Alexa Woods.

As a Predator ship reaches Earth's orbit, it blasts a shaft through the ice towards the source of the heat bloom. When the humans arrive at the site above the heat source, an abandoned whaling station, they find the shaft and descend beneath the ice. They discover a mysterious pyramid and begin to explore it, finding evidence of a civilization predating written history, when Antartica was free of ice, and what appears to be a sacrificial chamber filled with human skeletons with ruptured rib cages.

Meanwhile, three Predators land and kill the humans on the surface, making their way down to the pyramid and arriving just as the team unwittingly powers up the structure. An Alien queen awakes from cryogenic stasis and begins to produce eggs, from which facehuggers hatch and later attach to several humans trapped in the sacrificial chamber. Chestbursters emerge from these humans and they quickly grow into adult Aliens. Conflicts erupt then between the Predators, Aliens and the remaining humans, resulting in several deaths. Unbeknownst to the others, a Predator is also implanted with an Alien embryo.

Through translation of the pyramid's hyroglyphs, the explorers learn, that the Predators have been visiting Earth for thousands of years. It was they, who taught early human civilizations, how to build pyramids and they were also worshiped as gods by the early humans because of their capabilities, which were incredible for the humans back then. Every 100 years they would visit Earth to take part in a rite of passage in the pyramid, in which they would expect several humans to sacrifice themselves as hosts for the Aliens, creating the "ultimate prey" for the Predators to hunt, which they also did and, if overwhelmed, the Predators would then activate their self-destruct weapons to eliminate the Aliens and themselves. The explorers deduce, that this is why the current Predators are at the pyramid and that the heat bloom they detected was to attract humans for the purpose of making new Aliens to hunt for their rite of passage.

The remaining humans decide, reluctantly, that the Predators must be allowed to succeed in their hunt, so that the Aliens do not reach the surface, which would mean the end of humanity and themselves under the premise, the enemy of my enemy is my friend. Unfortunately, as the battle continues, almost all of the humans and Predators are killed, leaving only Alexa and a single Predator to fight against the Aliens. The two are forced to form an alliance and use the Predator's self-destruct device to destroy the pyramid and the remaining Aliens. Alexa and the Predator reach the surface, where they battle the escaped Alien queen. They defeat the queen by attaching its chain to a water tower and pushing it over a cliff into the water, dragging the queen to the ocean floor. The Predator, however, dies from its wounds.

A Predator ship uncloaks later and several Predators appear. They collect their fallen comrade and present with one of their spear weapons in recognition of her skills as a warrior. As they retreat into space, a chestburster with Predator-like features erupts from the dead Predator, beginning the events of Aliens vs Predator: Requiem.

Alien vs. Predator was first released in North America on August 13, 2004 in 3,395 theaters. It had a budget of $ 60 million and earned a total of $172 million. Alien vs. Predator received negative reviews from film critics, but it was more commercially successful than any of the preceding films in the Alien and Predator franchises, which led to the sequel in 2007 Aliens vs Predator: Requiem.